Method for preparing oxycodone

ABSTRACT

A method for the preparation of oxycodone, and salts thereof, from codeine comprising oxidation of codeine to codeinone, formation of an dienolsilyl ether congener of codeinone in strong amine base, oxidation of the dienolsilyl ether congener using peracetic acid, and hydrogenation of the resulting 14-hydroxycodeinone product.

BACKGROUND OF THE INVENTION

[0001] 1. Field of Invention

[0002] The present invention relates to an improved method for preparingoxycodone. More particularly, the present invention sets forth a methodfor preparing oxycodone in high yields that does not require theemployment, or synthesis, of thebaine in the reaction scheme.

[0003] 2. Background of the Related Art

[0004] The analgesic activity of Papaver somniferum has been known sinceantiquity. It has long been understood that the milky juice derived fromthe unripe seed capsules of this poppy plant possesses potentpharmacological properties. The dried and powdered form of the juice isreferred to as opium. Opium comprises about 10% of the juice obtainedfrom the unripe seed capsules of Papaver somniferum.

[0005] Early in the nineteenth century it was recognized that opiumcontains numerous alkaloid compounds. The first of these alkaloids to beisolated was morphine, described by Serturner in 1805. The isolation ofother alkaloids, including codeine (Robiquet 1832), papaverine (Merck1848), thebaine, oripavine and noscapine followed in short order. By themiddle of the nineteenth century, the use of pure alkaloids rather thancrude opium preparations was established medical practice. It is nowknown that opium contains more than twenty distinct alkaloids.

[0006] In general, the opium alkaloids can be divided into five distinctchemical classes: phenanthrene, benzylisoquinoline,tetrahydroisoquinoline, cryptopine and miscellaneous (Remington'sPharmaceutical Sciences 433, 1975). Therapeutically useful drugs areprimarily isolated from the phenanthrene and benzylisoquinoline classes.The principal phenanthrenes are morphine (≈10% of opium), codeine (≈0.5%of opium) and thebaine (≈0.2% of opium). The principalbenzylisoquinolines are papaverine (≈1.0% of opium) and noscapine (≈6.0%of opium).

[0007] Morphine itself comprises a 5-ring structure, incorporating apartially hydrogenated phenanthrene ring system. Each ring of morphineis designated as set forth below:

[0008] Morphine includes what is referred to in the art as a morphinanring structure, comprising rings A, B, C and E, as set forth below:

[0009] The substituent numbering of morphine derivatives follows twocommon conventions as shown:

[0010] It is the second (Chemical Abstracts) numbering system that shallbe made reference to hereinafter.

[0011] The first total synthesis of morphine was published in 1952(Gates, et al., 74 J. Amer. Chem. Soc., 1109, 1952). Because thelaboratory synthesis of morphine is difficult, however, the drug isstill obtained from opium or extracted from poppy straw (Goodman &Gilman's The Pharmacological Basis of Therapeutics, 489, 1990).Semi-synthetic derivatives of the naturally occurring opium alkaloidsare widely employed in medicine today. Among the important properties ofopioids that may be altered by structural modification are the affinityof the compound for various species of opioid receptors, resistance tometabolic breakdown, lipid solubility and agonist versus antagonistactivity.

[0012] Codeine, hydrocodone, hydromorphone, oxycodone, and oxymorphonewhich are found in present day analgesic prescription drugs, are allcongeners of morphine. Other structural analogs of morphine usedmedically in the United States include: levorphanol, nalmefene,naloxone, naltrexone, buprenorphine, butorphanol, and nalbuphine. Somemorphine analogs, such as levorphanol, may be produced totallysynthetically around a non-opiate morphinan nucleus which issynthesizable from coal tar derivatives (Remington's PharmaceuticalSciences 1039, 1975).

[0013] Among the many morphine structural analogs used in medicinetoday, widespread use is made of both codeine and oxycodone.

[0014] Codeine is 3-methylated morphine. Codeine has less thanone-seventh the analgesic potency of morphine (Foye, MedicinalChemistry, 254 (1975)). However, as codeine has a far better oralbioavailability than morphine (the 3-methoxy group is believed toprotect it from rapid first-pass biotransformation—the action ofmorphine orally is terminated largely by glucuronide conjugation at the3-hydroxyl group), codeine is only less than four times as potent, on aweight basis, than morphine when both compounds are administered orally(Drug Facts & Comparisons 1246, 1996). While some codeine is obtainedfrom opium directly, the quantity obtainable from such extraction is notsufficient to meet the extensive use of the alkaloid. The need forcodeine is fulfilled by partial synthesis of the compound from morphine(Remington's Pharmaceutical Sciences 1038, 1975).

[0015] Oxycodone is a white, odorless crystalline powder ofsemi-synthetic origin with multiple actions qualitatively similar tothose of morphine.

[0016] The principal actions of therapeutic value are analgesia andsedation. It is similar to codeine and methadone in that it retains atleast one half of its analgesic activity when administered orally. It isa pure agonist opioid, which produces not only analgesia, but othertherapeutic effects including anxiolysis, depression of the coughreflex, euphoria and feelings of relaxation. On a weight basis,oxycodone is approximately twice as potent orally as morphine (DrugFacts & Comparisons 1246, 1996). Oxycodone is typically indicated forthe relief of moderate to moderately severe pain (Drug Facts &Comparisons 1259, 1996).

[0017] Thebaine, which also contains a morphinan-ring structure, differsfrom codeine in replacing the hydroxyl group of the morphinan C-ringwith a methoxy group and the “C” ring has two double bonds—Δ^(6,7),Δ_(8,14) (i.e., thebaine differs from morphine in that both hydroxylgroups are methylated and the “C” ring has two double bonds—Δ^(6,7),Δ^(8,14)).

[0018] The compound demonstrates the effect that minor modifications instructure of morphinan compounds may have in pharmacological effects, asthebaine lacks any substantial analgesic activity (Foye, MedicinalChemistry, 256 (1975)).

[0019] While lacking medicinal usefulness in itself, thebaine issingularly important as a key intermediate in the synthesis of manyuseful opiate-derivatives (See, Barber et al., 18 J. Med. Chem.1074-107, 1975), including oxycodone (Freund et al., 94 J. Prak. Chemie135-178, 153, 1916; See Physician's Desk Reference, 2569, 54th Ed.1999), naloxone, naltrexone and nalbuphine (See, U.S. Pat. No. 4,795,813at Col. 1, lines 16-21). Thebaine is the only known Δ^(6,8)-dienecompound among the naturally-ocurring morphine alkaloids (Seiki, 18Chem. Pharm. Bull. 671-675, 1970).

[0020] Oxycodone may be prepared from thebaine by: dissolution of thethebaine in aqueous formic acid, oxidation treatment with 30% hydrogenperoxide (Seki, 18 Chem. Pharm. Bull. 671-676, 1970), neutralizationwith aqueous ammonia to yield 14-hydroxycodeinone and hydrogenation ofthe 14-hydroxycodeinone in acetic acid with the aid of apalladium-charcoal catalyst (Remington's Pharmaceutical Sciences 1041,1975). Oxidation of thebaine may alternatively be performed usingpotassium dichromate in acetic acid (Freund et al., 94 J. Prakt. Chem.135, 1916) or performic acid (Iljima et al., 60 Helv. Chim. Acta2135-2137, 1977). Improved yield, however, has been reported to beobtained by oxidizing with m-chloroperbenzoic acid in an aceticacid-trifluoroacetic acid mixture (Hauser et al., 17 J. Med. Chem. 1117,1974; See also, U.S. Pat. No. 4,795,813 to Schwartz, Col. 1, Lines22-26). Yield may also be improved by hydrogenation of14-hydroxycodeinone under a pressure of about 30 psi (Kraβnig et al. 329Arch. Pharm. Pharm. Med. Chem. 325-326, 1996).

[0021] Although particularly useful in the synthesis of numerouspharmaceutical preparations, thebaine is among the least abundantphenanthrene alkaloids in Papaver somniferum. Due to its scarcity, anumber of investigators have proposed methods of obtaining this uniquealkaloid using other more abundant opioid compounds as startingmaterials.

[0022] Seki (18 Chem. Pharm. Bull. 671-676, 1970) discloses a method forpreparing A^(6,8)-diene compounds, such as thebaine, fromα,β-unsaturated ketones such as codeinone, which may be obtained fromthe natural alkaloid codeine. Codeinone was added to a mixture ofp-toluenesulfonic acid (dehydrated prior to reaction), absolute methanoland dried benzene, the solution refluxed for 3 hours under azeotropicremoval of water, and the reaction mixture purified by washing withdiluted sodium hydroxide, to obtain thebaine. A reported maximum yieldof 26.8% was reported when using 1.1-0.15 molar equivalents ofp-toluenesulfonic acid to codeinone. Eppenberger et al. (51 Helv. Chim.Acta 381, 1968) report a four step method for convertingdihydrocodeinone to thebaine which results in a similar yield of 27%.Schwartz et al. (97 J. Am. Chem. Soc. 1239, 1975) demonstrate the totalsynthesis of thebaine in which the key step is the oxidative coupling ofa reticuline derivative to a salutaridine derivative. The overall yieldof dl-thebaine, however, was only in the 1-2% range based onisovanillin. Reaction of salutaridinol with an organic or inorganic acidhalide or acid anhydride, followed by treatment with a strong base, istaught as a method of thebaine production in U.S. Pat. No. 3,894,026 toSohar et al. A yield as high as 50.3% was reported (See, Col. 4, Line29). Barber et al. (18 J. Med. Chem. 1074-1077, 1975) reportsynthesizing thebaine (as well as oripavine) from codeine and morphine.Barber et al. teach methylation of the potassium salt of codeine to givecodeine methyl ether followed by oxidation with γ-MnO₂ (See also, U.S.Pat. No. 4,045,440 to Rapoport et al., 1977). These authors claim a 67%yield of oxycodone from codeine. European Patent Application No. EP 0889 045 A1 likewise teaches a process for the production of thebainefrom the more readily available morphinans codeine and morphine. Suchmethod provides for converting the starting material to an alkali metalor quaternary ammonium cation and reacting the same with a compound ofthe formula RX wherein R is an alkyl or acyl group and X is a leavinggroup.

[0023] While all of the above methods have been devised to increase thesupply of thebaine by synthetic and semi-synthetic means, the factremains that thebaine remains relatively costly as opposed to morphineand codeine.

[0024] The use of thebaine as a starting material to form othertherapeutically useful opioids also suffers from a disadvantageunassociated with its relative scarcity— thebaine is a known convulsant,capable of causing (even in low doses) strychnine-like convulsions(Foye, Principles of Medicinal Chemistry 255, 1975; The Merck Index,9203 (11th Edition), 1989). Employment of thebaine in any synthesisscheme, therefore, entails significant risks and requires the taking ofa number of precautions. Considering the relatively high cost of, andthe toxicity potential of, thebaine, it would be preferred ifalternative synthesis methods were developed to manufacture the manyopioid congeners currently synthesized from thebaine from cheaper andless toxic materials.

[0025] U.S. Pat. No. 2,654,756 discloses a method for converting codeineinto codeinone, dihydrocodeinone and dihydromorphine rather thansynthesizing such compounds from thebaine. Conversion is effectuated byway of oxidation using certain ketones in the presence of aluminumalkoxides. Likewise, methods for producing 14-hydroxymorphinans, such asnaloxone, naltrexone and nalbuphine (opioid antagonists) from codeine,without a thebaine intermediate, have also been disclosed (See, U.S.Pat. No. 4,472,253 to Schwarz and Schwartz and Wallace, 24 J. Med. Chem.1525-1528, 1981). To date, however, no economical method has beenproposed for manufacturing oxycodone from a readily available startingmaterial that has a toxicity and cost profile which is significantlyimproved over that possessed by thebaine.

BRIEF SUMMARY OF THE INVENTION

[0026] The present invention provides an improved, high-yield, methodfor preparing oxycodone that does not require employment of a thebaineintermediate in the reaction scheme. The disclosed method makes use ofcompound having a morphinan-like ring structure, such as codeine ormorphine, as a starting material for the synthesis of oxycodone. Themethod employs the steps of: converting the starting material to acompound with a morphinone ring structure, preparing a dienolsilyl etherat the C-ring of the morphinan-like ring structure by reacting anorganosilyl compound with the starting material, oxidizing the silylether, and hydrogenating the unsaturation in the C-ring. Formation ofthe dienolsilyl ether is promoted by efficient dienolization of theC-ring, which is provided by reacting the α,β-unsaturated ketone andorganochlorosilane reactants in the presence of a strong amine base,such as DBU (1,8-Diazabicyclo[5.4.0.]undec-7-ene) or DBN(1,5-Diazabicyclo[4.3.0]non-5-ene). Preferably the organosilyl reactant,for example a triorganosilyl chloride, is stericly hindered on thesilicone atom.

[0027] An aspect of the present invention comprises a method forproducing oxycodone from codeine employing two oxidation steps, oneinvolved in the oxidation of a hydroxyl group to a ketone, and the otherinvolving oxidative hydroxylation of a dienolsilyl ether. In particular,oxycodone free base has been produced in commercially reasonable yieldsby forming a dienolsilyl ether derivative of codienone in the presenceof a strong amine base (preferably a diazabicyclo-base), oxidizing thesilyl ether to form 14-hydroxycodeinone, and hydrogenation of themorphinan C-ring unsaturation to form oxycodone.

[0028] In one embodiment of the present invention, there is provided animproved method for synthesizing oxycodone from codeine free base. Inthis embodiment, codeine free base is converted to codeinone byoxidation, for example, by using a standard oxidant such as MnO₂,Na₂WO₄/H₂O₂, Pd(OAc)₂/O₂, and/or a standard oxidation procedure, e.g.,Swern/Moffat-type oxidation (DMSO-based oxidation), Oppenauer-typeoxidation (employing aluminum alkoxides and cyclohexanone or otherketones). Preferred oxidants include BaMnO₄ and Oppenauer oxidation.Codeinone is then reacted with an organosilyl compound having aneffective leaving group, such as a halogen. The resulting dienolsilylether derivative is then oxidized with an oxidizing agent to afford14-hydroxycodeinone. It has been found that the dienolsilyl ether of themorphinone C-ring may efficiently be converted to 14-hydroxycodeinoneusing peracetic acid solution. Hydrogenation of the unsaturation in theC-ring is subsequently performed and may be accomplished by way of, forexample, pressurized catalytic hydrogenation or catalytic transferhydrogenation in acetic acid. Oxycodone produced by such method has beenfound to be obtainable in yields approximating 80%.

[0029] One of the novelties of this invention is the discovery thatcommercially-practicable yields of therapeutically employed opioidalkaloids having a morphinan ring structure can be obtained withoutrecourse to a thebaine intermediate by reacting a compound with amorphinone ring structure with an organosilyl reactant in the presenceof a strong amine base, preferably a diazabicyclo-base such as DBU(1,8-Diazabicyclo[ 5.4.0.]undec-7-ene) or DBN(1,5-Diazabicyclo[4.3.0]non-5-ene) (to improve enolization and thepromotion of a dienolsilyl ether derivative), followed by oxidation ofthe dienolsilyl ether moiety.

DETAILED DESCRIPTION OF THE INVENTION AND PREFERRED EMBODIMENTS

[0030] After considerable experimentation with numerous reaction schemesdesigned to form oxycodone from codeine and morphine (two relativelyinexpensive opioid alkaloids), the present inventors have discovered aunique reaction scheme for manufacturing oxycodone that provides forindustrially-acceptable yields. The present invention overcomes many ofthe prior art problems associated with the production of oxycodone andprovides for a synthetic scheme for oxycodone production which does notemploy the relatively costly, scarce and toxic alkaloid—thebaine.

[0031] The present inventors have discovered that enolization of theC-ring of a morphinone compound having an α,β-unsaturated ketonestructure, is significantly enhanced by exposure to a strong amine base,such as DBU or DBN and similar diazabicyclo-bases. Formation of thedienolsilyl ether (by reaction with the ketone of such ring with aorganosilyl compound having an effective leaving group) was greatlyimproved by effectuating the reaction in the presence of the strongamine base. The present inventors have further discovered that thedienolsilyl ether of codeinone (the silyl ether formed at position 6(chemical abstract substituent-numbering designation)) may be used todirectly form 14-hydroxycodeinone by oxidation of the silyl ether. In apreferred embodiment, oxidation is performed at room temperature forabout 3 hours. The dienolsilyl ether of codeinone may be dissolved intoluene or other similar solvent. Oxidation may be efficiently performedwith relatively high yield using peracetic acid or other peracids.Hydrogenation of 14-hydroxycodeinone produces oxycodone. A preferredhydrogenation reaction employs hydrogen gas or NaH₂PO₂ along with apalladium-carbon catalyst, with the 14-hydroxycodeinone being dissolvedin a weakly acidic solution such as aqueous acetic acid.

[0032] A codeinone dienol silyl ether, such as the intermediate compoundformed in the conversion of codeine to oxycodone according to certainembodiments of the present invention, is disclosed in pending Europeanpatent application No. EP 0 889 Q45 A1 to Jen-Sen Dung. The reference,however, is instructive as to the unobviousness of the presentinvention.

[0033] Recognizing the expense and relative scarcity of thebaine, EP 0889 045 A1 teaches (as noted above) a process for the production ofthebaine and analogues thereof. While disclosing codeinonetert-butyldimethylsilyl dienol ether (Example 6), the patent teaches theproduction of oxycodone only from thebaine which is synthesized by theprocedures described (See, e.g., Abstract of the Disclosure, Col. 1,Lines 25-52, Col. 5, Lines 24-29, Col. 9, Example 8). No recognition ismade of the fact that the tert-butyldimethylsilyl dienol ether could beutilized, without synthesis of a thebaine intermediate, to produceoxycodone. Further the reference fails to teach a method for producingorganosilyl dienol ethers of the morphinone ring in commerciallypracticable yields. The reference notes that the codeinetert-butyldimethylsilyl dienol ether produced by the methods describedcomprised only 23% of the solid mass recovered (thus comprising arelatively minor component of the solid mass). EP 0 889 045 A1 does notdisclose or imply that yield could be significantly enhanced by thepresence of strong amine base (rather than tetrahydrofuran as taught bythe reference) in the reaction mix when the ether is being formed.

[0034] The presently disclosed invention provides commerciallypracticable yields, yields typically in excess of 50%, and moretypically in excess of 80%, of oxycodone from codeinone (a compound thatis easily obtained from codeine by oxidation). Codienone is easilysynthesized from codeine, an alkaloid that can be obtained naturally, orsemi-synthetically, as from morphine. It has been discovered that byreacting an organosilyl compound in the presence of a strong amine basethat a high degree of conversion to the organosilyl dienol etherconjugate of codeinone may be achieved. The strong amine base isbelieved to strong favor enolization of codeinone, a compound having anα,β-unsaturation in the “C” ring of the morphinone ring structure, whilethe organosilyl moiety captures the enol form. The organosilyl etherform of codeinone is also promoted by employing an organosilyl compoundhaving an effective leaving group, such as a halogen, and in employing astericly bulky silicone moiety. While the resulting dienolsilyl etherform of codeinone may be oxidized to 14-hydroxycodeinone using a numberof standard oxidizing agents, it has been found that oxidation withperacetic acid is extremely efficient, producing about an 80% yield. The14-hydroxycodeinone is then hydrogenated, as by catalytic hydrogenation,so as to hydrogenate the α,β-unsaturation of the C-ring. A catalytictransfer hydrogenation method in aqueous acetic acid was found toproduce about the same yield, and similar impurity patterns, as themethod reported by R. Kraβnig, et al.

[0035] In an aspect of the invention, there is disclosed a method ofproducing oxycodone from codeinone which comprises the steps of: (a)producing a dienol organosilyl ether at position 6 of the C-ring ofcodeinone thereby forming a dienol organosilyl ether congener ofcodeinone; (b) oxidizing the dienol organosilyl ether to form14-hydroxycodeinone; (c) hydrogenating the unsaturation in the C-ring of14-hydroxycodeinone to produce oxycodone.

[0036] The dienol organosilyl ether congener of codeinone is preferablyformed by reacting an organosilyl compound with codeinone, suchorganosilyl compound having the formula:

R₃ ³SiX

[0037] wherein R³ is alkyl or aryl and the three R³ groups may be thesame or different and X is a leaving group, such as imidazole, mesylate,tosylate or a halogen. Preferably, the organosilyl compound is reactedwith codeinone in the presence of a strong amine base, such asdiazobicyclo-base, for example, DBU(1,8-Diazabicyclo[5.4.0.]undec-7-ene) or DBN(1,5-Diazabicyclo[4.3.0]non-5-ene). Oxidation of the dienol organosilylether may be performed by treating the dienol organosilyl ether congenerof codeinone with peracetic acid, preferably in the presence of anorganic solvent such as toluene.

[0038] In another aspect of the present invention there is disclosed amethod for oxidizing a dienol silyl ether selected from the group havingthe formula:

[0039] wherein R¹ is selected from the group of alkyl or acyl and R² isselected from the group of lower alkyl, allyl, or lower alkylsubstituted by cycloalkyl, and R³ is an alkyl or aryl group and thethree R³ groups may be the same or different, which comprises the stepsof: (a) reacting the dienol silyl ether compound with peracetic acid and(b) thereafter a work up procedure to isolate the product as a freebase.

[0040] In yet another aspect of the present invention there is discloseda method for forming a dienol silyl ether selected from the group havingthe formula:

[0041] wherein R¹ is selected from the group of alkyl or acyl and R² isselected from the group of lower alkyl, allyl, or lower alkylsubstituted by cycloalkyl, and R³ is an alkyl or aryl group and thethree R³ groups may be the same or different, which comprises the stepsof:

[0042] reacting an morphinan-6-one selected from the group having theformula:

[0043] with an organosilyl compound having the formula

R₃ ³SiX

[0044] wherein R³ is an alkyl or aryl group and the three R³ groups maybe the same or different group and X is a leaving group, such asimidazole, mesyate, tosylate or a halogen, in the presence of a strongamine base. The strong amine base may be a diazabicyclo-base, and maymore specifically be selected from the group consisting of: DBU(1,8-Diazabicyclo[ 5.4.0.]undec-7-ene) and DBN(1,5-Diazabicyclo[4.3.0]non-5-ene). X is preferably chloride.

[0045] And yet another aspect of the present invention entails a methodof producing oxycodone from codeine which comprises the steps of: (a)oxidizing codeine to codeinone; (b) producing a dienol organosilyl etherat position 6 of the C-ring of codienone thereby forming a dienolorganosilyl ether congener of codeinone; (c) oxidizing the dienolorganosilyl ether to form 14-hydroxycodeinone; (d) hydrogenating theunsaturation in the C-ring of 14-hydroxycodeinone to produce oxycodone.The dienol organosilyl ether congener of codeinone of this embodimentmay be formed by reacting an organosilyl halide with codeinone,preferably an organosilyl halide having the formula: R³ ₃SiCl, whereinR³ is as defined hereinabove. Preferably the organosilyl chloride isreacted with codeinone in the presence of a strong amine base. Thestrong amine base may be a diazabicyclo-base and may be selected fromthe group consisting of: DBU (1,8-Diazabicyclo[ 5.4.0.]undec-7-ene) orDBN (1,5-Diazabicyclo[4.3.0]non-5-ene). The oxidation of the dienolorganosilyl ether may be performed by treating the dienol organosilylether congener of codeinone with peracetic acid (which reaction may becarried out in the presence of an organic solvent such as toluene).

[0046] A preferred method of the present invention for forming oxycodonefrom codeine fundamentally involves four (4) synthetic steps: (1)oxidation of codeine to codeinone; (2) formation of an organosilyl ethercongener of codeinone; (3) oxidation of the silyl ether to14-hydroxycodeinone; and (4) hydrogenation of the partially unsaturatednon-aromatic C-ring to produce oxycodone, such as described in moredetail below and as shown in the following diagrammatic form:

Oxidation of Codeine to Codeinone

[0047] The oxidation of codeine to codeinone may be performed bynumerous methods known to those of ordinary skill in the art including:CrO₃/TBHP oxidation, dichromate oxidation, Na₂WO₄/peroxide oxidation,BaFeO₄ oxidation, hydrous ZrO₂/ketone oxidation, oxidation using CrO₂,Highet oxidation (Highet et al., 77 J. Am. Chem. Soc. 4399, 1955) usingmanganese dioxide, Oppenauer oxidation using aluminum isopropoxide andcyclohexanone (See, U.S. Pat. No. 2,654,756 to Homeyer et al.), sodiumtungstate activated peroxide oxidation (Sato et al., 119 J. Am. Chem.Soc. 12386, 1997), Swern/Moffatt type (DMSO-based) oxidation, palladiumacetate catalyzed aerobic oxidation and barium manganate oxidation (See,Nishimura et al., 39 Tet. Let. 6011).

[0048] As would be understood by one of ordinary skill in the art, withrespect to any oxidation procedure, adjustment of reaction conditions,such as the concentration of the reactants, the acidity of the reactionmixture, the presence or absence of solvating agents, and the like, .mayimpact upon the yield of oxidized product. For example, with respect tobarium manganate oxidation it may be preferred to keep the reactionmixture at about 0° C. and to control the polarity of the solvent toimprove yield. With respect to Oppenauer oxidation, the addition oftoluene to the reaction scheme may improve yield, as well may azeotropicremoval of water from the codeine/toluene solution prior to the additionof a catalytic amount of aluminum isopropoxide, and the collection ofdistillate during and after the addition of the aluminum isopropoxide.Selection may also be made between numerous potential reactants such asin Swern/Moffatt type oxidation numerous activators in DMSO may beemployed including: oxalyl chloride, TsCl, P₂O₅, TFAA, Ac₂O, PySO₃,Ts₂O, SOCl₂, DCC, DIPC, cyanuric chloride, ClSO₂NCO, (MeSO₂)₂O, Cl₂, hotair, and the like.

Formation of Dienolsilyl Ether of Codeinone

[0049] Codeinone may be modified to form a silyl ether at position 6(Chemical Abstracts designation) by reaction with an organosilylcompound R₃ ³SiX. Preferred organosilyl compounds were found to bestericly-hindered at the silicon atom and to have chlorine as theleaving group. The enolized codeinone was efficiently trapped with atrialkychlorosilane, such as tert-butyldimethylchlorosilane ortriethylchlorosilane. The trimethylsilyl ether, however, was found to berapidly hydrolyzed. Enolization of codeinone, and the formation of thedienolsilyl ether, was found to be promoted by the presence of strongamine base, such as DBU or DBN. Other bases such as LDA, DABCO, DIPEA,TEA, imidazole, N-methylmorpholine, HMDS-Li salt, hexamethyldisilazane,and aluminum isopropoxide did not yield a desirable amount ofdienolsilyl ether.

Oxidation of Dienolsilyl Ether of Codeinone to 14-Hydroxycodeinone

[0050] Oxidation of the dienolsilyl ether of codeinone to14-hydroxycodeinone may be performed using the many oxidizing agents andmethods known in the art. For example, the dienolsilyl ether may beoxidized in a hydrogen peroxide-free performic acid mixture according tothe method published by Swern (D. Swern, Organic Reactions VII, 378,1953), by way of MnO₂ or performic acid. A preferred oxidationprocedure, however, was found to employ peracetic acid prepared fromacetic anhydride, hydrogen peroxide and a catalytic amount of sulfuricacid. Aging of the peracetic acid solution and treatment with aceticanhydride was found to improve optimum oxidation hydroxylation)presumably by removal of any free hydrogen peroxide. Anhydrous peraceticacid up to 25 days old was found to be most effective. The yield of14-hydroxycodeinone was found to be also effected by the molar ratio andpercentage of oxidant in the mixture. Optimal oxidation conditions mayvary with different organosilyl ethers. For example, the presence oftrifluoroacetic acid (TFA) was found to improve the oxidation of thetriethylsilyldienolate of codeinone. The isolation of14-hydroxycodeinone may entail de-activation of the spent peracetic acidby treating with either sodium hydrogen sulfite or sodium thiosulfateaqueous solution, and removal of acetic acid solvent (in vacuo), andorganic neutral by-products like disiloxane or silanol and N-oxide, byacid/base work up procedures. Oxidation of eithert-butyldimethylsilyldienolate or triethylsilyldienolate of codeinone mayafford a similar yield of 14-hydroxycodeinone (or its acid salt).Oxidation of the triethylsilyl dienol ether and t-butyldimethylsilylether of codeine with peracetic acid was found to produce yields of14-hydroxycodeinone in excess of about 80%.

Hydrogenation of 14-Hydroxycodeinone to Oxycodone

[0051] 14-Hydroxycodeinone was converted to oxycodone by hydrogenationof the α,β-unsaturation in the C-ring. Hydrogenation may be performed byusing any of the methods known for hydrogenation of 14-hydroxycodeinoneto oxycodone. For example, diphenylsilane and Pd(Ph₃P)/ZnCl₂ may be usedto reduce 14-hydroxycodeinone, as may sodium hypophosphite inconjunction with a Pd/C catalyst in aqueous acetic acid, and Pd/Ccatalytic transfer hydrogenation.

[0052] The following examples illustrate various aspects of the presentinvention. They are not, however, to be construed as limiting the claimsin any manner whatsoever.

EXAMPLE 1 Formation of Codeinone from Codeine

[0053] Codeinone was prepared by oxidation of codeine sulfatetrihydrate. A reaction mixture was prepared containing codeine sulfatetrihydrate (10.4 g), de-ionized water (20 g) and isopropyl acetate (87.2g) at ambient temperature. The reaction mixture was agitated and theresultant mixture cooled to about 20±5° C. Concentrated ammoniumhydroxide (18.0 g) was added in several portions and the mixture wasmaintained at a temperature of about 20±5° C. with stirring. Stirringwas continued for about 15 minutes, and then a small portion of theaqueous layer was withdrawn to check for pH value, which was to beadvantageously maintained between 11.0 and 12.0. The aqueous layer wasthen separated and re-extracted with isopropyl acetate (35 g). Thecombined organic layers (isopropyl acetate) were concentrated in vacuoto near dryness at temperature NMT 45° C. The residual isopropyl acetatesolvent was chased by adding 18 g of toluene. The concentration processwas then repeated in vacuo. Codeine free base dissolved in a mixture oftoluene (177 g) and cyclohexanone (47.4 g) at temperature NMT 45° C. wasthen transferred to the reaction flask which was equipped with magneticstirrer, thermocouple, Dean-Stark trap with condenser attached, additionfunnel with an extender (about 4 inches height), and a nitrogen-inletadapter. The mixture was heated to boiling temperature (about 116-118°C.) under a nitrogen atmosphere and 26 g (30 ml) of distillate werecollected in the Dean-Stark trap. A solution of aluminum isopropoxide(3.5 g) in 35.5 g (41 ml) of toluene was then added to the additionfunnel. The heating rate was adjusted and the aluminumisopropoxide/toluene solution was added into the reaction mixture atsuch a rate that the total volume was added over a 10-20 minute period(approximately the same volume (41 ml) of distillate was collected inthe Dean-Stark trap). After completion of the addition, collection ofthe distillate was continued such that 57 g (66 ml) of distillate wascollected in the Dean-Stark trap at a similar distillation rate. Theheat source was removed and the mixture allowed to cool down to ambienttemperature (under nitrogen atmosphere) over a period of about 30minutes. Reaction completeness was determined by withdrawing a smallsample from the batch, extracting it with a saturated sodium bicarbonatesolution and ethyl acetate, concentrating the organic layer,re-dissolving it with the HPLC mobile phase, and analyzing the sample onHPLC. The reaction was considered complete if the area % of codeine wasless than 3.5A %.

[0054] An aqueous solution of 13 wt. % Rochelle salt was then preparedby dissolving 19.5 g of potassium sodium tartrate tetrahydrate in 130.5g of de-ionized water at 20±5° C. The aqueous Rochelle salt solution (90ml) was added into the reaction mixture in one portion at ambienttemperature, the batch stirred for about 10 minutes, and filtered. Bothlayers were saved. The organic layer was washed with 60 ml of aqueousRochelle salt solution (both layers were saved). The organic layer waswashed with a mixture of 30 ml brine solution and 30 ml 5% sodiumbicarbonate solution (both layers were saved). All aqueous layers werethen combined and extracted with 43 g (50 ml) of toluene. The aqueouslayer was discarded. The organic layers were then combined andconcentrated in vacuo at temperature NMT 55° C. to near dryness.Twenty-two grams (25 ml) of toluene was added and the resultant organiclayer concentrated in vacuo twice more to remove residual cyclohexanone.Subsequently, 11.8 g (15 ml) of 2-propanol was added and the mixslurried at 0-5° C. for at least eight hours under a nitrogenatmosphere. Solids were then filtered and the flask/wet cake rinsed withthe chilled (about 5° C.) recycled filtrate. The latter operation wasrepeated until no solids were left in the flask. The chilled wet cakewas then rinsed with chilled (5-10° C.) 2-propanol (12 g, 15 ml), andfilter dried. The wet cake was then rinsed with heptane (6.8 g, 10 ml)and filter-dried. The resulting solids were vacuum dried at temperatureNMT 50° C. to a constant weight. A yield of 5.2 to 6.45 g (65.4 to81.2%) of off-white solids, with HPLC purity of about 96A %-99.3A % wasobtained. The compound was stored in a dark and cool place.

EXAMPLE 2 Preparation of Dienolsilyl Ether of Codeinone

[0055] Codeinone (6.0 g) with toluene (104 g) was added to a reactionflask equipped with a mechanical stirrer, thermocouple, Dean-Stark trapwith condenser attached, and a nitrogen-inlet adapter. The batch washeated to reflux and about 27.7 g (32 ml) of distillate was collected inthe Dean-Stark trap. The contents were then cooled to 20±5° C. under anitrogen atmosphere. A solution of DBU (4.22 g) in toluene (3 g) wasadded in one portion. Subsequently, a solution of t-BDMSiCl (4.22 g) intoluene (5 g) was likewise added in one portion. The batch was slowlywarmed to 58±3° C. and stirred at this temperature for about 2 hours.Completion of the reaction was adjudged by withdrawing a small samplefrom the batch, extracting it with a mixture of ethyl acetate andsaturated sodium bicarbonate solution, spotting the organic layer on aTLC plate, and then eluting it with a mobile phase of 9:1 mixture ofdichloromethane and methanol plus 3-4 drops of concentrated ammoniumhydroxide. If the reaction was determined to be incomplete, stirring wascontinued at 58±3° C. for an additional 2 hours and a TLC checkperformed once more. Alternatively reaction completion was accomplishedby adding about 5-10% more of both DBU and tBDMSiCl to the reactionmixture at the same temperature. The contents were then cooled to 20±5°C., and a mixture of 5% sodium bicarbonate solution (80 ml) and 60 ml ofwater was added in one portion. Stirring continued for about 10 minutes.The aqueous layer was then separated and discarded. The organic layerwas washed with a mixture of 50 ml brine and 50 ml saturated ammoniumchloride solution (the aqueous layers were discarded). The organic layerwas concentrated to near dryness in vacuo at temperature NMT 50° C., andthe residue diluted with 33.2 g of toluene to make up a 20 wt. % stocksolution. Yield was approximately quantitative. The stock solution wasfound to be stable at ambient temperature under nitrogen atmosphere forat least 6 months.

EXAMPLE 3 Preparation of Peracetic Acid Solution

[0056] 14-Hydroxycodeinone was synthesized from the dienolsilyl ether ofcodeinone by oxidative hydroxylation using a peracetic acid solutionpreparation. The peracetic acid solution was prepared as follows:

[0057] Acetic anhydride (80.0 g) and concentrated sulfuric acid (0.15 g,or about 6 drops) at ambient temperature were added to a clean and driedround bottom flask (3-neck, 250 ml) equipped with mechanical stirrer,thermocouple, nitrogen-inlet adapter and addition funnel. The mixturewas cooled to about 10±3° C. under a nitrogen atmosphere. A 14.0 g of30% aqeous hydrogen peroxide solution was slowly added through theaddition funnel. The addition of hydrogen peroxide was performed drop bydrop maintaining content temperature at NMT 27° C. (formation ofperacetic acid and the hydrolysis of acetic anhydride are stronglyexothermic, cooling is absolutely essential, but over-chilling the batchis not recommended). After complete addition, the batch was stirred forabout 30 minutes in a 10±3° C. bath. Acetic acid (10.0 g) was then addedthrough the addition funnel, and the batch slowly warmed to 25±5° C. Thebatch was then stirred for an additional hour (the batch should be keptin water bath all the time in order to avoid any unexpected exotherm).

EXAMPLE 4 Preparation of 14-Hydroxycodeinone from Dienolsilyl Ether ofCodeinone

[0058] Peracetic acid solution (107.7 g of 9.0 wt. % peracetic acid) atambient temperature (22±5° C.) was added to a reaction flask (3-neck,500 ml) equipped with mechanical stirrer and thermocouple,nitrogen-inlet adapter and addition funnel. A 20 wt. % stock solution ofthe dienolsilyl ether of codeinone (41.7 g) was added through theaddition funnel over a period of about 5 minutes and the temperature ofthe contents maintained at NMT 28° C. The batch was stirred at 22±5° C.for at least 3 hours. In order to test reaction completeness, a smallsample was withdrawn from the batch and quenched with saturated sodiumbicarbonate solution, and extracted with ethyl acetate. The EtOAc layerwas spotted onto a TLC plate and subsequently checked for thedisappearance of starting dienolsilyl ether of codeinone. The TLC mobilephase was a mixture of 95:5 of dichloromethane and methanol plus 3-5drops of concentrated ammonium hydroxide. If the reaction was adjudgedincomplete, the mixture was stirred at the same temperature for anadditional 2 hours then analyzed by TLC again. Alternatively completionof the reaction was pushed by the addition of 10 g of peracetic acid(9.0 wt. %) and stirring for an additional 1 h (analysis was then oncemore preformed using TLC).

[0059] Upon determination of the completion of the reaction 20.0 g of 10wt. % of aqueous sodium hydrogen sulfite solution was added in oneportion, and the resultant admixture stirred for 10 minutes at ambienttemperature. The batch was then concentrated in vacuo at temperature NMT45° C. to dryness. Subsequently water (180 g), toluene (69 g), ethylacetate (36 g) were added and vigorous stirring for about 10 minutesundertaken. The resulting layers were separated and the aqueous layersaved in a flask. The organic layer was washed thrice with a solution of26 ml of 2.5% HCl. The combined aqueous layers were then filteredthrough a pad of wet (with water) hyflo-supercel filter aid.Subsequently, EtOAc (85 g) was added to the filtrate and concentratedammonium hydroxide added in a quantity to adjust the pH of the aqueouslayer to about 11. The mixture was stirred for 10 minutes at about 60°C. and the layers were separated and saved. The aqueous layer was washedwith EtOAc (50 g) and then discarded. The combined organic layers wereconcentrated in vacuo to dryness at temperature NMT 50° C. To theresidue was added 2-propanol (13 g), and the resultant mixture stirredat 5-10° C. for at least 5 hours. The solids were filtered, the flaskand solids rinsed with the chilled (5° C.) filtrate followed by chilled(5-10° C.) 2-propanol (10 g) and heptane (8 g). The solid was thenvacuum dried at temperature NMT 50° C. to a constant weight. A yield ofbetween 3.50-4.96 g (55%-78%) of 14-hydroxycodeinone free base with apurity of over 96A % was obtained.

EXAMPLE 5 Preparation of Oxycodone from 14-Hydroxycodeinone by CatalyticHydrogenation

[0060] 14-Hydroxycodeinone (4.98 g) and acetic acid (155 g) were addedto a Parr shaker equipped with hydrogen inlet and outlet connectors. Themixture was shaken for about 5 minutes to completely dissolve the14-hydroxycodeinone at ambient temperature. The system was thenevacuated and the Parr shaker was filled with nitrogen. In one portion,under the nitrogen atmosphere, 10% Pd/C (50% water wet, 4.0 g) wasadded. The system was then evacuated, and was filled with hydrogen gasto a pressure of about 38 psi. The hydrogen inlet from the supply tankwas then closed and the mixture was shaken at an initial pressure of 38psi for about 3 hours (at ambient temperature). After 3 hours ofshaking, the system was evacuated and filled with nitrogen. The contentswere filtered over a hyflo-supercel filtering pad (3 g, wetted withwater). The Parr bottle and wet cake were then rinsed with acetic acid(2×21 g). The filtrate was concentrated in vacuo to dryness attemperature NMT 50° C. The residue was then dissolved with de-ionizedwater (50 g), and the pH adjusted to about 11.0 to 12.0 using 20%aqueous KOH solution and concentrated ammonium hydroxide (4 g). Themixture was then extracted with ethyl acetate (4×135 g), and thecombined organic layers concentrated in vacuo to dryness. A yield of3.51 to 4.26 g of crude oxycodone with HPLC purity of over 85A % (70.0to 85.0% yield) was obtained.

EXAMPLE 6 Preparation of Oxycodone from 14-Hydroxycodeinone by CatalyticTransfer Hydrogenation Method

[0061] 14-Hydroxycodeinone (4.98 g) and acetic acid (137 g) were addedto a reaction flask (3-neck, 250 ml) equipped with mechanical stirrer,addition funnel, thermocouple and nitrogen-inlet adapter. The system wasevacuated and the flask filled with nitrogen. Subsequently, 5% Pd/C (50%water wet, 3.0 g) in one portion was added under the nitrogenatmosphere. While the mixture was stirred for about 5 minutes at ambienttemperature (22±50° C.), a solution of sodium hypophosphite (6.0 g) inde-ionized water (25 g) was prepared. The aqueous sodium hypophosphitesolution was transferred into the addition funnel, and added to thereaction mixture over a period of about 30 minutes with maintenance ofcontent temperature at about 22±5° C. The mixture was then warmed toabout 45° C. and stirred for about 1 hour.

[0062] To determine the completeness of the reaction, a small sample waswithdrawn from the batch and the sample was filtered by means of asyringe filter into a mixture of ethyl acetate and saturated sodiumbicarbonate solution. After extraction, the organic layer wasconcentrated to dryness and the residue dissolved with HPLC mobilephase. The disappearance of 14-hydroxycodeinone was determined. If thereaction was discerned to be incomplete, the batch was stirred for anadditional 2 h period at 45° C., and the HPLC check performed once more.

[0063] Upon determination that the reaction was complete, the batch wascooled to ambient temperature (22±5° C.) under the nitrogen atmosphere,and the contents filtered over a hyflo-supercel filtering pad (3.0 g,wetted with water). The flask and wet cake were rinsed with acetic acid(20 g). The filtrate was concentrated in vacuo to near dryness attemperature NMT 50° C. The residue was dissolved with de-ionized water(50 g) and the pH adjusted to 11.0 to 12.0 with 20% aqueous KOH solutionand concentrated ammonium hydroxide (about 4 g). The mixture was thenextracted with ethyl acetate (4×135 g) and the combined organic layersconcentrated to dryness in vacuo. Crude oxycodone with an HPLC purity ofover 85A % was obtained in a yield of 70.0 to 85.0% (3.51 to 4.26 g).

[0064] While the invention has been described with respect to preferredembodiments, those skilled in the art will readily appreciate thatvarious changes and/or modifications can be made to the inventionwithout departing from the spirit or scope of the invention as definedby the appended claims.

What is claimed is:
 1. A method of producing oxycodone from codeinonewhich comprises the steps of: (a) producing a dienol organosilyl etherat position 6 of the C-ring of codeinone thereby forming a dienolorganosilyl ether congener of codeinone; (b) oxidizing the dienolorganosilyl ether to form 14-hydroxycodeinone; and (c) hydrogenating theunsaturation in the C-ring of 14-hydroxycodeinone to produce oxycodone.2. The method of claim 1 wherein the dienol organosilyl ether congenerof codeinone is formed by reacting an organosilyl compound withcodeinone.
 3. The method of claim 2 wherein the organosilyl compound hasthe formula: R₃ ³SiX wherein R³ is an alkyl or aryl group and the threeR³ groups are the same or different, and X is a leaving group selectedfrom imidazole, mesylate, tosylate or halogen.
 4. The method of claim 3wherein R³ is selected from the group consisting of C₁-C₄ alkyl orphenyl and X is chloro.
 5. The method of claim 2 wherein the organosilylhalide is reacted with codeinone in the presence of a strong amine base.6. The method of claim 5 wherein the strong amine base is DBU(1,8-Diazabicyclo[ 5.4.0.]undec-7-ene) or DBN(1,5-Diazabicyclo[4.3.0]non-5-ene).
 7. The method of claim 1 wherein theoxidation of the dienol organosilyl ether is performed by treating thedienol organosilyl ether congener of codeinone with peracetic acid. 8.The method of claim 7 wherein the treatment with peracetic acid iscarried out in the presence of an organic solvent.
 9. The method ofclaim 8 wherein the organic solvent is toluene.
 10. A process ofproducing 14-hydroxycodeinone from codeinone comprising reacting anorganosilyl halide in the presence of a strong amine base and oxidizingthe resulting product with peracetic acid.
 11. The process of claim 10wherein the strong amine base is a diazobicyclo-base.
 12. The process ofclaim 11 wherein the strong amine base is selected from the groupconsisting of: DBU (1,8-Diazabicyclo[5.4.0.]undec-7-ene) and DBN(1,5-Diazabicyclo[4.3.0]non-5-ene).
 13. A method for oxidizing a dienolsilyl ether selected from the group having the formula:

wherein R¹ is alkyl or acyl, R₂ is lower alkyl, allyl, or lower alkylsubstituted by cycloalkyl, and R³ is an alkyl or aryl group and thethree R³ groups are the same or different which comprises the steps of:(a) reacting the dienol silyl ether compound with peracetic acid and (b)thereafter isolating the product as a free base.
 14. A method forforming a dienol silyl ether selected from the group having the formula:

wherein R¹ is of alkyl or acyl, R₂ is lower alkyl, allyl, or lower alkylsubstituted by cycloalkyl, and R³ is an alkyl or aryl group and thethree R³ groups are the same or different which comprises the steps of:reacting an morphinan-6-one selected from the group having the formula:

 with an organosilyl compound having the formula R₃ ³SiX  wherein R³ isas defined above and X is a leaving group selected from imidazole,mesylate, tosylate or halogen, in the presence of a strong amine baseand an aprotic solvent.
 15. The method of claim 14 wherein the strongamine base is a diazabicylco-base.
 16. The method of claim 15 whereinthe diazabicyclo-base is selected from the group consisting of: DBU(1,8-Diazabicyclo[5.4.0.]undec-7-ene) and DBN(1,5-Diazabicyclo[4.3.0]non-5-ene).
 17. The method of claim 14 whereinR³ is C₁-C₄ alkyl or phenyl.
 18. The method of claim 14 wherein X ischloride.
 19. A method of producing oxycodone from codeine whichcomprises the steps of: (a) oxidizing codeine to codeinone; (b)producing a dienol organosilyl ether at position 6 of the C-ring ofcodeinone thereby forming a dienol organosilyl ether congener ofcodeinone; (c) oxidizing the dienol organosilyl ether to form14-hydroxycodeinone; and (d) hydrogenating the unsaturation in theC-ring of 14-hydroxycodeinone to produce oxycodone.
 20. The method ofclaim 19 wherein the dienol organosilyl ether congener of codeinone isformed by reacting an organosilyl halide with codeinone.
 21. The methodof claim 20 wherein the organosilyl halide has the formula: R₃ ³SiClwherein R³ is C₁-C₄ alkyl or phenyl.
 22. The method of claim 20 whereinthe organosilyl halide is reacted with codeinone in the presence of astrong amine base.
 23. The method of claim 22 wherein the strong aminebase is DBU (1,8-Diazabicyclo[5.4.0.]undec-7-ene) or DBN(1,5-Diazabicyclo[4.3.0]non-5-ene).
 24. The method of claim 19 whereinthe oxidation of the dienol organosilyl ether is performed by treatingthe dienol organosilyl ether congener of codeinone with peracetic acid.25. The method of claim 24 wherein the treatment with peracetic acid iscarried out in the presence of an organic solvent.
 26. The method ofclaim 25 wherein the organic solvent is toluene.